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Abstract Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients.

Abstract Exosomes, a specific subset of extracellular vesicles, have diverse functions in various biological processes. In the field of cancer research, there has been a growing interest in the potential of exosomes to act as versatile vehicles for targeted tumor imaging and therapy. In this study, we constructed a targeted delivery platform using hypoimmunogenic exosomes by genetically modifying β2‐microglobulin knocking‐out HEK‐293F cells to express a fusion protein, referred to as αMUC1‐Exo, which comprises the exosomal membrane‐enriched platelet‐derived growth factor receptor, intracellular nanoluciferase, and extracellular anti‐MUC1 single‐chain variable fragment. The findings of this study indicate that αMUC1‐Exos exhibited notable drug delivery properties toward MUC1‐positive pancreatic cancer cells, resulting in a substantial inhibition of tumor growth. Moreover, these exosomes demonstrated a high level of biosafety and the absence of any adverse effects. The application of engineered exosomes as a vehicle for drug delivery holds promise for enhancing the immunogenicity of neoplastic cells following treatment, thereby inducing antitumor immune memory in mice with intact immune systems, and also improving the response to anti‐PD1 therapy. This approach utilizing engineered exosomes for Gemcitabine administration holds promise as a potential strategy for overcoming drug resistance in pancreatic carcinoma thereby improving the overall treatment efficacy.

Abstract Hepatocellular carcinoma (HCC) is a form of malignancy with limited curative options available. To improve therapeutic outcomes, it is imperative to develop novel, potent therapeutic modalities. Ketoconazole (KET) has shown excellent therapeutic efficacy against HCC by eliciting apoptosis. However, its limited water solubility hampers its application in clinical treatment. Herein, a mitochondria‐targeted chemo‐photodynamic nanoplatform, CS@KET/P780 NPs, is designed using a nanoprecipitation strategy by integrating a newly synthesized mitochondria‐targeted photosensitizer (P780) and chemotherapeutic agent KET coated with chondroitin sulfate (CS) to amplify HCC therapy. In this nanoplatform, CS confers tumor‐targeted and subsequently pH‐responsive drug delivery behavior by binding to glycoprotein CD44, leading to the release of P780 and KET. Mechanistically, following laser irradiation, P780 targets and destroys mitochondrial integrity, thus inducing apoptosis through the enhancement of reactive oxygen species (ROS) buildup. Meanwhile, KET‐induced apoptosis synergistically enhances the anticancer effect of P780. In addition, tumor cells undergoing apoptosis can trigger immunogenic cell death (ICD) and a longer‐term antitumor response by releasing tumor‐associated antigens (TAAs) and damage‐associated molecular patterns (DAMPs), which together contribute to improved therapeutic outcomes in HCC. Taken together, CS@KET/P780 NPs improve the bioavailability of KET and exhibit excellent therapeutic efficacy against HCC by exerting chemophototherapy and antitumor immunity.

Abstract Background Sexually dimorphic mating behaviors differ between sexes and involve gonadal hormones and possibly sexually dimorphic gene expression in the brain. However, the associations among the brain, gonad, and sexual behavior in teleosts are still unclear. Here, we utilized germ cells-free tdrd12 knockout (KO) zebrafish, and steroid synthesis enzyme cyp17a1-deficient zebrafish to investigate the differences and interplays in the brain–gonad–behavior axis, and the molecular control of brain dimorphism and male mating behaviors. Methods Tdrd12 +/−; cyp17a1 +/− double heterozygous parents were crossed to obtain tdrd12 −/− ; cyp17a1 +/+ (tdrd12 KO), tdrd12 +/+; cyp17a1 −/− (cyp17a1 KO), and tdrd12 −/− ; cyp17a1 −/− (double KO) homozygous progenies. Comparative analysis of mating behaviors were evaluated using Viewpoint zebrafish tracking software and sexual traits were thoroughly characterized based on anatomical and histological experiments in these KOs and wild types. The steroid hormone levels (testosterone, 11-ketotestosterone and 17β-estradiol) in the brains, gonads, and serum were measured using ELISA kits. To achieve a higher resolution view of the differences in region-specific expression patterns of the brain, the brains of these KOs, and control male and female fish were dissected into three regions: the forebrain, midbrain, and hindbrain for transcriptomic analysis. Results Qualitative analysis of mating behaviors demonstrated that tdrd12 −/− fish behaved in the same manner as wild-type males to trigger oviposition behavior, while cyp17a1 −/− and double knockout (KO) fish did not exhibit these behaviors. Based on the observation of sex characteristics, mating behaviors and hormone levels in these mutants, we found that the maintenance of secondary sex characteristics and male mating behavior did not depend on the presence of germ cells; rather, they depended mainly on the 11-ketotestosterone and testosterone levels secreted into the brain–gonad regulatory axis. RNA-seq analysis of different brain regions revealed that the brain transcript profile of tdrd12 −/− fish was similar to that of wild-type males, especially in the forebrain and midbrain. However, the brain transcript profiles of cyp17a1 −/− and double KO fish were distinct from those of wild-type males and were partially biased towards the expression pattern of the female brain. Our results revealed important candidate genes and signaling pathways, such as synaptic signaling/neurotransmission, MAPK signaling, and steroid hormone pathways, that shape brain dimorphism and modulate male mating behavior in zebrafish. Conclusions Our results provide comprehensive analyses and new insights regarding the endogenous interactions in the brain–gonad–behavior axis. Moreover, this study revealed the crucial candidate genes and neural signaling pathways of different brain regions that are involved in modulating brain dimorphism and male mating behavior in zebrafish, which would significantly light up the understanding the neuroendocrine and molecular mechanisms modulating brain dimorphism and male mating behavior in zebrafish and other teleost fish. Graphical Abstract

Abstract Background Lung cancer is one of the most frequent causes of cancer-related deaths worldwide. Drug repurposing and nano-drug delivery systems are attracting considerable attention for improving anti-cancer therapy. Sertaconazole (STZ), an antifungal agent, has been reported to exhibit cytotoxicity against both normal and tumor cells, and its medical use is limited by its poor solubility. In order to overcome such shortcomings, we prepared a drug-repurposed nanoplatform to enhance the anti-tumor efficiency. Methods Nanoplatform was prepared by thin film dispersion. Drug release studies and uptake studies were measured in vitro. Subsequently, we verified the tumor inhibition mechanisms of HTS NPs through apoptosis assay, immunoblotting and reactive oxygen species (ROS) detection analyses. Antitumor activity was evaluated on an established xenograft lung cancer model in vivo. Results Our nanoplatform improved the solubility of sertaconazole and increased its accumulation in tumor cells. Mechanistically, HTS NPs was dependent on ROS-mediated apoptosis and pro-apoptotic autophagy to achieve their excellent anti-tumor effects. Furthermore, HTS NPs also showed strong inhibitory ability in nude mouse xenograft models without significant side effects. Conclusions Our results suggest that sertaconazole-repurposed nanoplatform provides an effective strategy for lung cancer treatment.

ABSTRACTAcne vulgaris caused by antibiotic-resistant Cutibacterium acnes (C. acnes) infection is difficult to treat conventionally. Phages have been suggested as a potential solution, but research on the mechanism of phage treatment is inadequate. This research investigates the underlying molecular mechanisms of phage φPaP11-13 attenuating C. acnes-induced inflammation in rat models. We found that rats infected with C. acnes had higher average ear thickness, greater enrichment of inflammatory cells as shown by hematoxylin–eosin (HE) staining, and fewer TUNEL (TdT-mediated dUTP Nick-End Labeling)-positive keratinocytes visualized by IF staining. Moreover, an increase of IGF-1 and IGF-1 receptor (IGF-1r) was detected using the immunohistochemical (IHC) staining method, Western blot (WB), and quantitative real-time PCR (qRT-PCR) when infected with C. acnes, which was decreased after the application of phage φPaP11-13. By applying the IGF-1 antibody, it was demonstrated that the severity of C. acnes-induced inflammation was relevant to the expression of IGF-1. Through WB and qRT-PCR, activation of the PI3K/Akt pathway and a down-regulation of the BAD-mediated apoptosis pathway were discovered after C. acnes infection. Subsequently, it was shown that the activation of the PI3K/Akt pathway against BAD-mediated apoptosis pathway was alleviated after applying phage φPaP11-13. Furthermore, applying the IGF-1r inhibitor, Pan-PI3K inhibitor, and Akt inhibitor reversed the changing trends of BAD induced by C. acnes and phage φPaP11-13. This study demonstrates that one of the critical mechanisms underlying the attenuation of acne vulgaris by phage φPaP11-13 is lysing C. acnes and regulating keratinocyte apoptosis via the PI3K/Akt signaling pathway.IMPORTANCECutibacterium acnes infection-induced acne vulgaris may cause severe physical and psychological prognosis. However, the overuse of antibiotics develops drug resistance, bringing challenges in treating Cutibacterium acnes. Bacteriophages are currently proven effective in MDR (multiple drug-resistant) Cutibacterium acnes, but there is a significant lack of understanding of phage therapy. This study demonstrated a novel way of curing acne vulgaris by using phages through promoting cell death of excessive keratinocytes in acne lesions by lysing Cutibacterium acnes. However, the regulation of this cell cycle has not been proven to be directly mediated by phages. The hint of ternary relation among "phage–bacteria–host" inspires huge interest in future phage therapy studies.

Abstract Background Using a rotary instrument or ultrasonic instrument for tooth preparation is a basic operation in the dental clinic that can produce a significant number of droplets and aerosols. The dental droplet and aerosol can lead to the transfer of harmful germs. The goal of this study was to analyze the properties of microbiological aerosol created by droplets and aerosol generated by three common tooth-preparation instruments. Methods Streptococcus mutans UA159 was used as the biological tracer to visualize the droplets and aerosols. The passive sampling method was used to map the three-dimensional spatial distribution and the six-stage Andersen microbial sampler (AMS) was used as the active sampling method to catch aerosol particles at a specific time. Results The aerosol concentration is related to instruments, three-dimensional spatial distribution, and dissipation time. Most aerosols were generated by air turbines. More microorganisms are concentrated at the 1.5 m plane. The majority of the post dental procedure contamination was detected within the 0–10-min period and it decreased rapidly within 30 min. Conclusion This study is conducive to the proposal and improvement of relevant infection control measures in dental procedures and provides a basis for the assessment of measures, reducing the risk of nosocomial infection.

IntroductionPseudomonas aeruginosa (P.aeruginosa) is an important opportunistic pathogen with broad environmental adaptability and complex drug resistance. Single-molecule real-time (SMRT) sequencing technique has longer read-length sequences, more accuracy, and the ability to identify epigenetic DNA alterations.MethodsThis study applied SMRT technology to sequence a clinical strain P. aeruginosa PA3 to obtain its genome sequence and methylation modification information. Genomic, comparative, pan-genomic, and epigenetic analyses of PA3 were conducted.ResultsGeneral genome annotations of PA3 were discovered, as well as information about virulence factors, regulatory proteins (RPs), secreted proteins, type II toxin-antitoxin (TA) pairs, and genomic islands. A genome-wide comparison revealed that PA3 was comparable to other P. aeruginosa strains in terms of identity, but varied in areas of horizontal gene transfer (HGT). Phylogenetic analysis showed that PA3 was closely related to P. aeruginosa 60503 and P. aeruginosa 8380. P. aeruginosa's pan-genome consists of a core genome of roughly 4,300 genes and an accessory genome of at least 5,500 genes. The results of the epigenetic analysis identified one main methylation sites, N6-methyladenosine (m6A) and 1 motif (CATNNNNNNNTCCT/AGGANNNNNNNATG). 16 meaningful methylated sites were picked. Among these, purH, phaZ, and lexA are of great significance playing an important role in the drug resistance and biological environment adaptability of PA3, and the targeting of these genes may benefit further antibacterial studies.DisucssionThis study provided a detailed visualization and DNA methylation information of the PA3 genome and set a foundation for subsequent research into the molecular mechanism of DNA methyltransferase-controlled P. aeruginosa pathogenicity.

Introduction1α,25-dihydroxyvitamin D3 (1α,25[OH]2VD3) is a hormone known for its key roles in calcium absorption and nutrient metabolism. In teleost fishes, 1α,25(OH)2VD3 insufficiency causes impaired glucose metabolism and lipid oxidation. However, the cascade and mechanisms of 1α,25(OH)2VD3 and the vitamin d receptor (VDR) signaling are unclear.ResultsIn this study, two genes (vdra and vdrb) encoding paralogs of VDRs were genetically knocked out in zebrafish. Growth retardation and accumulated visceral adipose tissue have been observed in vdra-/-;vdrb-/- deficient line. In the liver elevated accumulation of triglycerides and suppressed lipid oxidation were detected. Morover significantly elevated 1α,25(OH)2VD3 levels were detected in vdra-/-;vdrb-/- zebrafish due to cyp24a1 transcription repression. Furthermore VDRs ablation Enhanced insulin signaling including elevated insulin/insra trancriptional levels, glycolysis, lipogenesis and promoted AKT/mTOR activity.DiscussionIn conclusion, our present studies provides a zebrafish model with an elevated 1α,25(OH)2VD3 levels in vivo. The 1α,25(OH)2VD3/VDRs signaling promote lipid oxidation activity. However 1α,25(OH)2VD3 activity of regulation of glucose homeostasis through Insulin/Insr was independent of nuclear VDRs in teleosts.

Background: The clinical applications of stromal vascular fraction (SVF) therapy for osteoarthritis (OA) have attracted academic and clinical attention. However, data of the effects of stromal vascular fraction therapy on regeneration of degenerated cartilage are limited in the literature. Meanwhile, there is a great need for a simple and non-invasive evaluation method to analyze the changes of joint cartilage qualitatively and quantitatively in clinical trials. This study entitled “stromal vascular fraction Therapy for Human Knee Osteoarthritis” was registered in ClinicalTrial.gov # NCT05019378.Materials and Methods: We designed and conducted a single center, open labeled clinical phase I/II study, and 6 osteoarthritis patients with both knee cartilage defect I-II were enrolled in this study. The two knees of each patient were randomly assigned to autologous stromal vascular fraction treatment group or non-treatment control group to evaluate the safety and therapeutic effect of stromal vascular fraction therapy for human knee osteoarthritis. We have also established a novel protocol to provide 3D MRI imaging for human knee cartilage enabling us to qualitatively and quantitatively evaluate cartilage degeneration and regeneration in this study.Results: The qualitative and quantitative evaluation of 3D Magnetic Resonance Imaging (MRI) imaging of knee cartilage demonstrated that the stromal vascular fraction therapy reduced the cartilage defects; and significant increase of cartilage value both in defect cartilage area and whole cartilage area of treated group and significant increase of thickness and area of both femoral and tibia cartilage in vertical sections of the stromal vascular fraction treated Group at 12 and 24 W post treatment in cartilage defect I-II osteoarthritis patients.Conclusion: This clinical phase I/II study indicated that stromal vascular fraction therapy is a safe clinical procedure and provided evidence that the stromal vascular fraction therapy significantly facilitated cartilage regeneration, opening the opportunity to a phase III trial investigating authentic efficacy of the procedure. This study is the first qualitative and quantitative evaluation of the efficacy of autologous stromal vascular fraction cellular therapy on cartilage regeneration. Through early and definite diagnosis of knee osteoarthritis patients, and providing safe and efficient therapy to facilitate cartilage regeneration, we will be able to control or reverse cartilage degeneration and completely change the epidemiology of osteoarthritis worldwide.

Antibiotics-resistant Propionibacterium acne (P. acne) causes severe acne vulgaris, serious public health, and psychological threat. A new lytic bacteriophage (phage), φPaP11-13, infecting P. acne, was isolated from the sewage management center of Xinqiao Hospital. It can form transparent plaque with diameters of 1.0 ~ 5.0 mm on the double-layer agar plate, indicating a robust lytic ability against its host. Transmission electron microscopy (TEM) showed that φPaP11-13 belonged to the Siphoviridae family (head diameter 60 ± 4.5 nm, tail length 170 ± 6.4 nm, tail width 14 ± 2.4 nm). The one-step growth curve showed the incubation period was 5 h, and the burst size was 26 PFU (plaque-forming unit)/cell. Moreover, it exhibited tolerance over a broad range of pH and temperature ranges but was utterly inactivated by ultraviolet (UV) irradiation for 1 h. The whole-genome sequencing results revealed φPaP11-13 had a linear dsDNA with 29,648 bp length. The G/C content was 54.08%. Non-coding RNA genes and virulence factors were not found. Forty five open reading frames (ORFs) were identified after online annotation. This study reports a novel P. acne phage φPaP11-13, which has a robust lytic ability, no virulence factors, and good stability. The characterization and genomic analysis of φPaP11-13 will develop our understanding of phage biology and diversity and provide a potential arsenal for controlling antibiotics-resistant P. acne-induced severe acne vulgaris.

The goal of this work is to analyze how double inversion layers affect fog–haze events and boundary layers over Eastern China based on unmanned aerial vehicle observations. During 10–12 December 2020, two successive fog–haze events occurred in Eastern China. Based on the unmanned aerial vehicle (UAV), wind, temperature, relative humidity (RH), and aerosol mass concentration were monitored simultaneously in Lianyungang, China. Several observations were found after analyzing the physical fields of these data. The results show that the concentrations of air pollutants during fog events were negatively correlated with horizontal visibilities. The mass concentrations of particulate matter increased rapidly (After 08:00 BJT 11) in the fog dissipation stages (PM2.5 and PM10 increased from 97 and 150 μg/m3 to 213 and 300 μg/m3, respectively). Double temperature inversion significantly affected fog events, where the enhancement of the lower-level temperature inversion (where the inversion layer top height was between 150 and 300 m) corresponded to the explosive growth of fog and the dissipation of the upper-level inversion layer. (The bottom height of the inversion layer was between 350 m and 600 m) This indicates the end of fog events. Fog layer thicknesses are negatively correlated with the concentrations of air pollutants in the near-surface layer. The thickening of the inversion layer near the surface corresponds to an increase (after 05:00 BJT 11 and 03:00 BJT 12) in fog layer height. The fog event is maintained when water vapor conditions are favorable enough or when there is a deep near-surface temperature inversion but the maintenance of the near-surface temperature inversion at an intensity of above 2 °C (100 m)−1 mainly contributes to the durations of these two fog events. Calculations through the trajectory model reveal that the air pollutant source varied during these two events, which was the main reason for the difference in air pollutant concentrations between the two events.

Nannochloropsis has been considered as a promising feedstock for the industrial production of violaxanthin. However, a rational breeding strategy for the enhancement of violaxanthin content in this microalga is still vacant, thereby limiting its industrial application. All-trans-lycopene locates in the first branch point of carotenogenesis. The carotenoid isomerase (CRTISO), catalyzing the lycopene formation, is thus regarded as a key enzyme for carotenogenesis. Phaeodactylum tricornutum can accumulate high-level carotenoids under optimal conditions. Therefore, it is feasible to improve violaxanthin level in Nannochloropsis by overexpression of PtCRTISO. Protein targeting analysis of seven PtCRTISO candidates (PtCRTISO1–6 and PtCRTISO-like) demonstrated that PtCRTISO4 was most likely the carotenoid isomerase of P. tricornutum. Moreover, the transcriptional pattern of PtCRTISO4 at different cultivation periods was quite similar to other known carotenogenesis genes. Thus, PtCRTISO4 was transformed into N. oceanica. Compared to the wild type (WT), all three transgenic lines (T1–T3) of N. oceanica exhibited higher levels of total carotenoid and violaxanthin. Notably, T3 exhibited the peak violaxanthin content of 4.48 mg g–1 dry cell weight (DCW), which was 1.68-folds higher than WT. Interestingly, qRT-polymerase chain reaction (PCR) results demonstrated that phytoene synthase (NoPSY) rather than ζ-carotene desaturase (NoZDS) and lycopene β-cyclase (NoLCYB) exhibited the highest upregulation, suggesting that PtCRTISO4 played an additional regulatory role in terms of carotenoid accumulation. Moreover, PtCRTISO4 overexpression increased C18:1n-9 but decreased C16:1n-7, implying that C18:1 may serve as a main feedstock for xanthophyll esterification in Nannochloropsis. Our results will provide valuable information for the violaxanthin production from Nannochloropsis.

Based on the air temperature, wind speed, humidity, air pressure, etc., of the regional automatic weather station in Chutouling Town, Jizhou from April 2019 to November 2020, and the air temperature of the microclimate observation station receiving data every 10 min in a bailing mushroom greenhouse, this paper analyzed and evaluated a BP (back propagation) neural network and stepwise regression method to establish a prediction model for the temperature in the Bailing mushroom greenhouse for different seasons. The results showed that: (1) The air temperature, wind speed, humidity and air pressure outside the shed were the main factors for building the temperature prediction model for the inside temperature, and the air temperature was the most important factor affecting the temperature inside the shed. After introducing humidity, wind speed and air pressure, the accuracy of the model was significantly improved. (2) The temperature prediction model based on the BP neural network method, for every 10 min interval in the greenhouse, for the Bailing mushroom in different seasons, was more accurate than the stepwise regression model. The simulation results of the two models had the highest accuracy in summer, followed by autumn. (3) The root means square error of the BP neural network and stepwise regression model for inside the greenhouse, simulating the daily temperature variations for different seasons, was 1.25, 1.10, 1.08, 1.31 °C and 1.29, 1.19, 1.11, 1.37 °C, respectively. The BP neural network method performed better for predicting the daily temperature variations in seasons. (4) The specifying data of high temperature (24 July 2020) and strong cold wave (31 December 2019) were selected to test the two model methods; the results showed that the simulation of the BP neural network model was better than the stepwise regression model.

The availability of the new generation Integrated Multi-satellitE Retrievals for Global Precipitation Measurement (IMERG) V06 products facilitates the utility of long-term higher spatial and temporal resolution precipitation data (0.1° × 0.1° and half-hourly) for monitoring and modeling extreme hydrological events in data-sparse watersheds. This study aims to evaluate the utility of IMERG Final run (IMERG-F), Late run (IMERG-L) and Early run (IMERG-E) products, in flood simulations and frequency analyses over the Mishui basin in Southern China during 2000–2017, in comparison with their predecessors, the Tropical Rainfall Measuring Mission Multi-satellite Precipitation Analysis (TMPA) products (3B42RT and 3B42V7). First, the accuracy of the five satellite precipitation products (SPPs) for daily precipitation and extreme precipitation events estimation was systematically compared by using high-density gauge station observations. Once completed, the modeling capability of the SPPs in daily streamflow simulations and flood event simulations, using a grid-based Xinanjiang model, was assessed. Finally, the flood frequency analysis utility of the SPPs was evaluated. The assessment of the daily precipitation accuracy shows that IMERG-F has the optimum statistical performance, with the highest CC (0.71) and the lowest RMSE (8.7 mm), respectively. In evaluating extreme precipitation events, among the IMERG series, IMERG-E exhibits the most noticeable variation while IMERG-L and IMERG-F display a relatively low variation. The 3B42RT exhibits a severe inaccuracy and the improvement of 3B42V7 over 3B42RT is comparatively limited. Concerning the daily streamflow simulations, IMERG-F demonstrates a superior performance while 3B42V7 tends to seriously underestimate the streamflow. With regards to the simulations of flood events, IMERG-F has performed optimally, with an average DC of 0.83. Among the near-real-time SPPs, IMERG-L outperforms IMERG-E and 3B42RT over most floods, attaining a mean DC of 0.81. Furthermore, IMERG-L performs the best in the flood frequency analyses, where bias is within 15% for return periods ranging from 2–100 years. This study is expected to contribute practical guidance to the new generation of SPPs for extreme precipitation monitoring and flood simulations as well as promoting the hydro-meteorological applications.

Immunotherapy is an effective treatment option that revolutionizes the management of various cancers. Nevertheless, only a subset of patients receiving immunotherapy exhibit durable responses. Recently, numerous studies have shown that oxidative stress induced by reactive oxygen species (ROS) plays essential regulatory roles in the tumor immune response, thus regulating immunotherapeutic effects. Specifically, studies have revealed key roles of ROS in promoting the release of tumor-associated antigens, manipulating antigen presentation and recognition, regulating immune cell phenotypic differentiation, increasing immune cell tumor infiltration, preventing immune escape and diminishing immune suppression. In the present study, we briefly summarize the main classes of cancer immunotherapeutic strategies and discuss the interplay between oxidative stress and anticancer immunity, with an emphasis on the molecular mechanisms underlying the oxidative stress-regulated treatment response to cancer immunotherapy. Moreover, we highlight the therapeutic opportunities of manipulating oxidative stress to improve the antitumor immune response, which may improve the clinical outcome.

Tobacco mosaic virus (TMV), a widespread plant pathogen, is found in tobacco (including cigarettes and smokeless tobacco) as well as in many other plants. Plant viruses do not replicate or cause infection in humans or other mammals. This study was done to determine whether exposure to tobacco products induces an immune response to TMV in humans. Using a sandwich ELISA assay, we detected serum anti-TMV antibodies (IgG, IgG1, IgG3, IgG4, IgA, and IgM) in all subjects enrolled in the study (20 healthy smokers, 20 smokeless-tobacco users, and 20 non-smokers). Smokers had a higher level of serum anti-TMV IgG antibodies than non-smokers, while the serum level of anti-TMV IgA from smokeless tobacco users was lower than smokers and non-smokers. Using bioinformatics, we also found that the human protein TOMM40L (an outer mitochondrial membrane 40 homolog--like translocase) contains a strong homology of six contiguous amino acids to the TMV coat protein, and TOMM40L peptide exhibited cross-reactivity with anti-TMV antibodies. People who smoke cigarettes or other tobacco products experience a lower risk of developing Parkinson's disease, but the mechanism by which this occurs is unclear. Our results showing molecular mimicry between TMV and human TOMM40L raise the question as to whether TMV has a potential role in smokers against Parkinson's disease development. The potential mechanisms of molecular mimicry between plant viruses and human disease should be further explored.

A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.

Antibiotics-resistant Propionibacterium acne (P. acne) causes severe acne vulgaris, serious public health, and psychological threat. A new lytic bacteriophage (phage), φPaP11-13, infecting P. acne, was isolated from the sewage management center of Xinqiao Hospital. It can form transparent plaque with diameters of 1.0 ~ 5.0 mm on the double-layer agar plate, indicating a robust lytic ability against its host. Transmission electron microscopy (TEM) showed that φPaP11-13 belonged to the Siphoviridae family (head diameter 60 ± 4.5 nm, tail length 170 ± 6.4 nm, tail width 14 ± 2.4 nm). The one-step growth curve showed the incubation period was 5 h, and the burst size was 26 PFU (plaque-forming unit)/cell. Moreover, it exhibited tolerance over a broad range of pH and temperature ranges but was utterly inactivated by ultraviolet (UV) irradiation for 1 h. The whole-genome sequencing results revealed φPaP11-13 had a linear dsDNA with 29,648 bp length. The G/C content was 54.08%. Non-coding RNA genes and virulence factors were not found. Forty five open reading frames (ORFs) were identified after online annotation. This study reports a novel P. acne phage φPaP11-13, which has a robust lytic ability, no virulence factors, and good stability. The characterization and genomic analysis of φPaP11-13 will develop our understanding of phage biology and diversity and provide a potential arsenal for controlling antibiotics-resistant P. acne-induced severe acne vulgaris. [ABSTRACT FROM AUTHOR]

The article focuses on the study conducted to examine the Interleukin-2 or Interleukin-2 antibody therapy induces targeting organ natural killer cells. It states that the natural killer (NK) cells might provide insight into the mechanism of action of multiple sclerosis (MS) therapies. It concludes that the immunotherapeutic potential of NK cells, act as critical suppressor cells in target organs of autoimmunity.

Mechanisms underlying the clinical benefits of glatiramer acetate (GA) for patients with multiple sclerosis (MS) remain elusive. A prevailing hypothesis is that GA can induce Th2-polarized T cells, which cross-recognize myelin-specific epitopes and can inhibit myelin-reactive autoaggression in Th1 T cells, a process referred to as ‘bystander suppression.’ To test whether the efficacy of GA is indeed mediated by Th2 T cells, we have utilized an animal model for MS: experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. GA therapy conferred moderate protection from EAE. GA-reactive T cells from these mice were not Th2 polarized, and the Th1 cytokine reduction of myelin-reactive T cells in GA-treated mice was comparable to that in untreated control mice. Significantly, the protective effects of GA against EAE were also observed in IL-4-, IL-10-deficient and IL-4/IL-10 double-deficient mice. Similar to wild-type mice, GA therapy in IL-4- and IL-10-deficient mice was associated with diminished myelin-reactive T cell expansion and reduced production of myelin antigen-induced IFN-γ and tumor necrosis factor-α. Thus, despite the absence of two prominent Th2 cytokines, IL-4 and IL-10, either alone or combined, GA was still beneficial in suppressing EAE. Our results caution against the notion that Th2 cells and bystander suppression account for the effect of GA on EAE and suggest that an alternative mechanism may operate in GA-treated MS patients. [ABSTRACT FROM AUTHOR]

Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by ≈50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species. [ABSTRACT FROM AUTHOR]